The present invention is directed to a method and apparatus for controlling the administration of an hypnotic drug in “closed loop” fashion.
An hypnotic drug may comprise an anesthetic agent and the hypnotic state induced in a patient by the administration of such a drug in one of anesthetization. An hypnotic drug typically acts on the brain to produce a lessening or loss of consciousness in the patient. The extent to which the patient is anesthetized is often termed the “hypnotic level” or “depth of anesthesia.” In the present invention, the existing hypnotic level, or depth of anesthesia, in the patient is sensed and used to control the hypnotic drug administration to the patient in the manner of a closed loop, or feedback, regulator to achieve and maintain a desired level in the patient.
More particularly, the present invention employs the complexity of electroencephalographic (EEG) data obtained from the patient as a sensed indication of the hypnotic level of the patient for use in controlling hypnotic drug administration. The use of such an indication provides closed loop control of drug administration that is based on an accurate assessment of the hypnotic condition of the patient and one that is highly responsive to changes in that condition. Such an indication can be made rapidly responsive to changes in the hypnotic condition of the patient.
Hypnotic drugs, or anesthetic agents, are administered by inhalation or intravenously. When administration is by inhalation, the anesthetic agent comprises a volatile liquid that is vaporized in a vaporizer. The vaporized anesthetic agent is entrained in breathing gases for the patient. The concentration of the anesthetic agent supplied by the vaporizer is determined by the anesthesiologist by manipulating appropriate controls on the vaporizer. The concentration of anesthetic agent in the lungs of the patient may be measured by measuring the amount of anesthetic agent contained in the breathing gases exhaled by the patient at the end of the exhalation phase of the respiratory cycle, i.e. the end tidal concentration (ETconc). Typical inhaled anesthetic agents are sevoflurane, enflurane, and desflurane, among others.
In a simple form, intravenous administration of an hypnotic drug may employ a syringe that injects the drug into a vein of the patient. For extended administration, a motor driven syringe or a motor driven infusion pump may be employed. A commonly used, intravenously administered, anesthetic agent is propofol.
In addition to hypnosis, high quality anesthesia must also consider loss of sensation (analgesia), muscle relaxation, suppression of the autonomous nervous system, and blockage of the neuro muscular function. This may require administration of a number of different drugs via the same or different routes. Further, different hypnotic drugs and/or different administration routes may be used at different stages of an anesthetization or a medical procedure. For example, hypnosis may be introduced by an intravenously administered drug and maintained by an inhaled drug.
In the process by which a drug, including a hypnotic drug, takes its effect in the body, two aspects are important: pharmacokinetics and pharmacodynamics. Pharmacokinetics  Pharmacodynamics deals with the effect of the body on the drug, such as the body's absorption, distribution or diffusion, metabolism, and excretion of the drug. Pharmacokinetics describes how the drug is distributed in the course of time from the site of delivery to different parts of the body and to a particular organ in which the drug is supposed to have its effect.
For use in the study of drugs, the determination of dosages, and the like, mathematical models have been developed for the pharmacokinetics of a drug. Because of the complexity of the physiology of the body, the models are typically based on theoretical compartments, such as plasma, fat, or the brain. Pharmacokinetic models typically allow for consideration of anthropometric data, such as patient height, weight, age, sex, etc. Pharmacokinetic models are available for hypnotic drugs, or anesthetic agents, including propofol, based on two or more different compartments. See Shafer, et al. Anesthesiology, 1998; 69:348-356 describing a two compartment model for propofol.
When a specific effect of a drug can be directly or indirectly measured, such data can be used to define a pharmacodynamic model of the drug with respect to its concentration at the site at which it is effective, i.e. effect-site concentration. Such models may also use anthropometric data. For hypnotic drugs the effect is the hypnotic state of the patient and the effect-site in the brain.
In a broad sense, all hypnotic drug administration is of a controlled loop nature. In a basic form, an anesthesiologist administers such a drug to a patient, observes the state of the patient resulting from the administration of the drug, and then maintains or alters the dose based on his/her observations. However, in a more specific sense, reflecting recent work in the field of anesthesia, closed loop control relates to the sensing of the hypnotic state of the patient by some form of instrumentation and automatically controlling the administration of the drug responsive to a feedback signal from the instrumentation. The term is used herein in the more specific sense.
The interest in closed loop control is posited, at least in part, on a desire to accurately establish the hypnotic level or depth of anesthesia of the patient. If the anesthesia is not sufficiently deep, the patient may maintain or gain consciousness during a surgery, or other medical procedure, resulting in an extremely traumatic experience for the patient, anesthesiologist, and surgeon. On the other hand, excessively deep anesthesia reflects an unnecessary consumption of hypnotic drugs, most of which are expensive. Anesthesia that is too deep requires increased medical supervision during the surgery recovery process and prolongs the period required for the patient to become completely free of the effects of the drug.
Rapidity is another desirable feature of an hypnotic drug administration control system. Fast response is particularly desirable should the patient approach consciousness since, as noted above, unexpected emergence is to be avoided, but is rendered more likely as excessively deep anesthesia is avoided.
A closed loop hypnotic drug delivery system has been described using the bispectral index as a control parameter. See Mortier E., et al. Anesthesia, 1998, August; 53 (8):749-754. See also published European Patent Application No. EP 959,921 to authors of this article. The bispectral index is proprietary to Aspect Medical Systems of Farmingham, Mass. and is described in one or more of the following U.S. Pat. Nos.: 4,907,597; 5,101,891; 5,320,109; and 5,458,117. The bispectral index is an effort to form a single variable, termed the bispectral index (BIS), that correlates behavioral assessments of sedation and hypnosis over a range of anesthesia for several hypnotic drugs.
The bispectral index comprises three components that are combined in various ways to provide an indication over a range of hypnotic levels from light sedation to deep anesthesia. See Ira R. Rampil, “A Primer for EEG Signal Processing in Anesthesia”, Anesthesiology 89 (1998), 980-1002. See also U.S. patent application, Ser. No. 09/688,891 to an inventor named herein and another, assigned to a common assignee, also containing a description of this index.
In order to compute a BIS value, measured EEG data over a period of fifteen seconds is used. During anesthesia, the level of painful stimulation can vary drastically and cause rapid changes in the hypnotic level of the patient, i.e. wake the patient up. Because of the time required to compute a BIS value, the bispectral index may not be sufficiently rapid to warn the anesthesiologist that this is occurring. Also, the bispectral index is contaminated by electromyographic (EMG) activity which may lead to misjudgment of the hypnotic level of a patient. See Bruhn J., et al., Anesthesiology 2000; 92:1485-7. Certain paradoxical behavior of the bispectral index (BIS) not connected to EMG has also been reported; see Detsch O. et al., British Journal of Anesthesia 84 (1):33-7 (2000); Hirota K. et al., Eur J Anaesth 1999, 16, 779-783.
Another approach to closed loop or feedback control of hypnotic drug administration is disclosed in published International Patent Appln. WO 98/10701 by Mantzaridis, et al. In the technique of the patent, the patient is fitted with headphones and is subjected to noise in the form of “clicks” of one ms duration at a frequency of 6.9 Hz. The auditory evoked potential (AEP) resulting from this stimulation, and more particularly, the alteration of the delay between the auditory stimulus and the auditory stem response in the brain is used in this method to evaluate the level of hypnosis of a patient during anesthesia. While an AEP index has been shown to distinguish between the conscious and unconscious states of a patient in an accurate manner, the correlation with drug concentration is not as good and has been reported as poorer than that for the bispectral index. See Doi M, et al., Br J Anaesth. 1997, February; 78(2):180-4. The auditory response does not persist to the lowest hypnotic levels, restricting the range of measurement. This tends to lessen the utility of the AEP index for use in closed loop hypnotic drug administration. Also, the technique requires placing earphones on the patient and is limited to patients having adequate hearing.
U.S. Pat. No. 6,016,444 to E. R. John, describes another method using information extracted from EEG signal data to control a closed-loop drug delivery system. The parameters mentioned include EEG spectral powers measured in different frequency ranges and the spectral edge frequencies, below which are found, for example, 50% or 90% of the total power spectrum. In addition to the EEG spectrum derived parameters, the method also uses brain wave evoked responses, such as brain stem or cortical auditory evoked responses, which may bear a correlation to anesthesia level. Electrodes are applied to the front and back of the scalp and the method essentially compares the derived features between these locations using covariance matrices. After the patient has been anesthetized and when he/she has obtained the plane of anesthesia desired by the anesthesiologist, a form of calibration procedure called “self-normalization” is carried out. The plane of anesthesia is determined by clinical signals observed by the anesthesiologist. After self-normalization, the system tries to maintain the anesthetic level of the patient established during that procedure as the set point.
The need for the self-normalization procedure presents a disadvantage to this procedure in that the anesthesiologist may forget to carry it out or carry it out at the wrong plane of anesthesia. In the time period required for the procedure, which according to the patent preferably lasts for 60 seconds, the condition of the patient may change. Also, there is no published evidence that the particular EEG-derived parameters chosen for measurement correlate very well with hypnotic levels.